This proposal, in response to the RFA CA-98-028 Early Detection Research Network/Biomarkers Developmental Laboratories (EDRN/BDL), is an integrated multi-disciplinary project of the University of Pittsburgh Cancer Institute (UPCI) bringing together faculty with relevant expertise in key disease sites including bladder, colorectal, lung/aerodigestive tract, and ovarian cancer. For each site, a lead Co-Investigator and research group, with ongoing interactions among basic cancer researchers, biostatisticians, clinicians, surgeons, and pathologists, have proposed innovative approaches to the discovery of new early cancer detection/susceptibility biomarkers and refinement and initial validation of panels of recently described biomarkers. In addition, two research groups with molecular genetics expertise in the characterization of cancer gene mutations and metabolic enzyme/DNA repair gene polymorphisms will apply these endpoints in collaborative studies in several organ sites. These studies utilize the extensive UPCI clinical infrastructure and pathology resources necessary for the collection, histopathological characterization, and processing of tissue/biological fluid samples built, in part, upon UPCI's participation in the initial EDR Network. Specific biomarkers to be investigated in this project include a unique BLCA-4 protein immunoassay in urine for early detection of bladder cancer; LOH for 5q, mutation in K-ras and exon 15 of APC, and expression of iNOS and COX-2 as early detection markers of colorectal carcinoma; SAGE analysis of ovarian tumors for discovery of peripheral blood-based immunoassay markers; ras and p53 gene mutations in lung/airway biopsy samples and EGF and GRP receptor expression in buccal mucosa and peripheral blood as early detection biomarkers of HNSCC and NSCLC; and application of genotyping assays for CYP1A1, GSTM1, GSTT1, MPO, and NAT2 together with the development and validation of new assays for the recently-described polymorphisms in the DNA nucleotide excision repair (NER) genes XPD and XPF as risk susceptibility markers for bladder, colorectal, and/or lung/aerodigestive cancer. These research activities will be conducted in the context of an active integrated UPCI EDRN/BDL program, facilitated by the Principal Investigator who brings extensive experience and UPCI programmatic leadership in research and molecular epidemiological application of biomarkers, in an environment focused on a collaborative process of cancer biomarkers discovery, evaluation, and validation to support the broader research and clinical goals of the EDRN.